The broad, long-term objectives of this research are to identify specific roles for matallothionein (MT) in mammalian species, particularly with respect to two important areas: (1) biochemical pathways for handling toxic heavy metals and (2) molecular responses to ionizing radiation an toxic metals. The proposed research focuses on the hypothesis that the MTs are highly inducible proteins that, throughout evolution, have provided protection against adverse environmental conditions, including those involving heavy metals (either excesses or deficiencies) and ionizing radiation. Because diet is the main source of human exposure to toxic metals in the environment, the proposed research will study the role of MT in the gastrointestinal (GI) absorption of toxic metals, in particular cadmium. Because of enhanced susceptibilities of fetal and neonatal tissues to toxic metals, the potentially important role of MT in cadmium transfer from dam to offspring will also be addressed. Finally, our extensive experience with ionizing radiation and cadmium will be applied to determine the role of MT in molecular responses to these carcinogenic agents. The approach uses the recently developed mouse strain in which both alleles of MT-1 and MT-II are inactivated (MT-knockout mice (Ma94). The Specific Aims are to make use of MT-knockout (MT-KO) mice (Ma94) and MT-normal (MT-N) controls to determine the role of MT in; (1) Pathways of cadmium intestinal absorption and transfer from dam to offspring--pathways that are integral to defining target organ toxicities. (2) Molecular responses to radiation and cadmium, measured by changes in early gene expression and mutation frequency. Our guiding hypothesis is that MT-KO mice will (a) have altered metabolic pathways for transfering oral cadmium across the GI tract and for transfering cadmium from mother to offspring and (b) show increased sensitivity to radiation- and cadmium-induced gene changes that may be involved in carcinogenesis. Results of the proposed research will yield definitive insight into the function of MT in decreasing damage from toxic heavy metals and ionizing radiation -- two functions that appear to have been critical during evolution. Evaluation of MT's potential for decreasing transfer of Cd from mother to offspring will provide insight into protective pathways in women environmentally exposed to heavy metals during pregnancy and lactation.